Immunization with live, replication-competent Ad-HIV or Ad-SIV envelope recombinant vaccines primes strong antibody responses that develop following administration of booster immunizations with envelope protein. These antibodies display a variety of functional activities. The most desirable for an HIV/AIDS vaccine is neutralizing activity that is able to prevent infection following exposure to the virus. We have elicited such antibodies in the rhesus macaque model that conferred apparent sterilizing immunity following challenge with an HIV/SIV chimeric SHIV virus. Our vaccine regimen also elicits antibodies with other functional activities mediated by Fc-receptor bearing cells such as NK cells. HIV/SIV infection is initially manifested as small foci of infected cells. Within 2 to 6 days, virus spreads from these cell foci to draining lymph nodes, subsequently leading to systemic infection. These additional functional activities can help control the initial viral burden by limiting the spread of virus from these foci of infection. Such activities include antibody dependent cellular cytotoxicity (ADCC), antibody dependent cell-mediated viral inhibition (ADCVI), and antibody-dependent cellular phagocytosis (ADCP). In addition, antibody-dependent complement mediated lysis of virus and virus infected cells is a potential functional activity that can contribute to overall protection, as is ADCP mediated by neutrophils. Since HIV is transmitted mainly at rectal/genital mucosal sites, a key goal of HIV vaccine development is to elicit mucosal immunity. The Ad-recombinant prime/protein boost strategy induces antibodies in mucosal secretions which can inhibit transcytosis of SIV across an epithelial cell barrier, suggesting another mechanism which may contribute to protection. These mechanisms are all currently under study. Recently we completed a pre-clinical vaccine study using the SIV-rhesus macaque model in which we uncovered a sex bias in vaccine-induced protection. Vaccinated female macaques, but not males, exhibited delayed SIV acquisition. We showed that vaccine-induced SIV envelope-specific mucosal IgA, Envelope-specific memory B cells, and total rectal plasma cells were correlated with this protective outcome. Subsequently we showed that female macaques developed better quality antibodies of the IgG3 subtype which is more effective in mediating protective antibody responses. Moreover, male macaques exhibited a greater proportion of B regulatory cells associated with suppression and suggesting that these cells might have facilitated infection in the males. Ongoing studies are investigating cytokines secreted by B cells, as these molecules have the ability to regulate immune B cell responses. We have also examined plasma cell niche factors in bone marrow and the rectal mucosa in order to better understand the accumulation of plasma cells in the mucosa. Investigation of the sex bias in vaccine-induced protection is important as approximately 50% of HIV infected individuals are women. A current pre-clinical study in the macaque model is on-going to determine if the sex bias outcome can be reproduced. Finally, an in depth investigation of the non-neutralizing ADCP activity of V2 monoclonal antibodies has been conducted. V2 antibodies were identified as a protective immune correlate in the RV144 clinical vaccine trial, the only trial to have reached any degree of protective efficacy. Although V2 antibodies have been associated with protection, the mechanism(s) by which they confer protection has remained unidentified. We have recently found that V2 monoclonal antibodies mediate ADCP activity, suggesting a mechanism which may contribute to protection. Continued studies of B cell development and maturation, with a special focus on germinal center B cells in the lymph node, are on-going.